1. Field of the Invention
The present invention relates to preparation of microparticles containing an active agent. More particularly, the present invention relates to microparticles having a selected release profile for release of the active agent from the microparticles, and to a method for the preparation of such microparticles.
2. Related Art
A variety of methods is known by which compounds can be encapuslated in the form of microparticles. It is particularly advantageous to encapsulate a biologically active or pharmaceutically active agent within a biocompatible, biodegradable wall-forming material (e.g., a polymer) to provide sustained or delayed release of drugs or other active agents. In these methods, the material to be encapsulated (drugs or other active agents) is generally dissolved, dispersed, or emulsified in a solvent containing the wall forming material. Solvent is then removed from the microparticles to form the finished microparticle product.
An example of a conventional microencapsulation process is disclosed in U.S. Pat. No. 3,737,337 wherein a solution of a wall or shell forming polymeric material in a solvent is prepared. The solvent is only partially miscible in water. A solid or core material is dissolved or dispersed in the polymer-containing solution and, thereafter, the core-material-polymer-containing solution is dispersed in an aqueous liquid that is immiscible in the organic solvent in order to remove solvent from the microparticles.
Tice et al. in U.S. Pat. No. 4,389,330 describe the preparation of microparticles containing an active agent by using a two-step solvent removal process. In the Tice et al. process, the active agent and the polymer are dissolved in a solvent. The mixture of ingredients in the solvent is then emulsified in a continuous-phase processing medium that is immiscible with the solvent. A dispersion of microparticles containing the indicated ingredients is formed in the continuous-phase medium by mechanical agitation of the mixed materials. From this dispersion, the organic solvent can be partially removed in the first step of the solvent removal process. After the first stage, the dispersed microparticles are isolated from the continuous-phase processing medium by any convenient means of separation. Following the isolation, the remainder of the solvent in the microparticles is removed by extraction. After the remainder of the solvent has been removed from the microparticles, they are dried by exposure to air or by other conventional drying techniques.
Another conventional method of microencapsulating an agent to form a microencapsulated product is disclosed in U.S. Pat. No. 5,407,609. This method includes: (1) dissolving or otherwise dispersing one or more agents (liquids or solids) in a solvent containing one or more dissolved wall-forming materials or excipients (usually the wall-forming material or excipient is a polymer dissolved in a polymer solvent); (2) dispersing the agent/polymer-solvent mixture (the discontinuous phase) into a processing medium (the continuous phase which is preferably saturated with polymer solvent) to form an emulsion; and (3) transferring all of the emulsion immediately to a large volume of processing medium or other suitable extraction medium, to immediately extract the solvent from the microdroplets in the emulsion to form a microencapsulated product, such as microcapsules or microspheres.
U.S. Pat. No. 5,650,173, the entirety of which is incorporated herein by reference, discloses a process for preparing biodegradable, biocompatible microparticles comprising a biodegradable, biocompatible polymeric binder and a biologically active agent, wherein a blend of at least two substantially non-toxic solvents, free of halogenated hydrocarbons, are used to dissolve both the agent and the polymer. The solvent blend containing the dissolved agent and polymer is dispersed in an aqueous solution to form droplets. The resulting emulsion is added to an aqueous extraction medium preferably containing at least one of the solvents of the blend, whereby the rate of extraction of each solvent is controlled, whereupon the biodegradable, biocompatible microparticles containing the biologically active agent are formed. Active agents suitable for encapsulation by this process include, but are not limited to, norethindrone, risperidone, and testosterone, and a preferred solvent blend is one comprising benzyl alcohol and ethyl acetate.
U.S. Pat. No. 5,654,008, the entirety of which is incorporated herein by reference, describes a microencapsulation process that uses a static mixer. A first phase, comprising an active agent and a polymer, and a second phase are pumped through a static mixer into a quench liquid to form microparticles containing the active agent.
The documents described above all disclose methods that can be used to prepare microparticles that contain an active agent. As explained, for example, in U.S. Pat. No. 5,650,173, by appropriately selecting the polymeric materials, a microparticle formulation can be made in which the resulting microparticles exhibit both diffusional release and biodegradation release properties. For a diffusional mechanism of release, the active agent is released from the microparticles prior to substantial degradation of the polymer. The active agent can also be released from the microparticles as the polymeric excipient erodes. However, none of the foregoing documents disclose a specific method for preparing microparticles that have a selected release profile for release of the active agent from the microparticles.
Thus, there is a need in the art for a method for preparing microparticles having a selected release profile for release of active agent in the microparticles in accordance with the selected release profile. There is a further need in the art for a method for controlling the release profile of the active agent contained in microparticles. The present invention, the description of which is fully set forth below, solves the need in the art for such methods.
The present invention relates to an improved method for preparing microparticles that exhibit controlled release of an effective amount of an active agent over an extended period of time. More particularly, the present invention relates to a method for preparing microparticles having a selected release profile for release of active agent contained in the microparticles. In one aspect, the method of the present invention comprises: preparing an emulsion that comprises a first phase and a second phase, the first phase comprising the active agent, a polymer, and a solvent for the polymer; quenching the emulsion in a quench liquid to form microparticles containing the active agent; and performing a degree of intermediate drying of the microparticles so that the selected release profile is achieved. If the degree of intermediate drying performed is no intermediate drying, then the resulting microparticles have an initial burst and a substantially linear release profile. If the degree of intermediate drying performed is substantially complete intermediate drying, then the resulting microparticles have an initial lag phase and a substantially sigmoidal release profile.
In a further aspect of the present invention, the method further comprises, after the intermediate drying step, the steps of washing the microparticles and final drying the microparticles. In a preferred aspect of the invention, the washing step is carried out by: introducing the microparticles into a vessel containing an extraction medium having a temperature lower than the glass transition temperature of the microparticles; agitating the vessel contents to disperse the microparticles in the extraction medium; and transferring the microparticles from the vessel to an extraction tank having another extraction medium having a temperature higher than the glass transition temperature of the microparticles at the time of transfer of the microparticles.
In yet another aspect of the invention, a method for controlling a release profile of an active agent contained in microparticles is provided. The method comprises: forming microparticles containing the active agent by quenching an emulsion in a quench liquid, the emulsion comprising a first phase and a second phase, the first phase comprising the active agent, a polymer, and a solvent for the polymer; and adjusting a degree of drying of the microparticles, the degree of drying affecting the release profile of the active agent from the microparticles. In a further aspect, the degree of drying is adjusted to comprise no intermediate drying, thereby resulting in an initial burst of the active agent and a substantially linear release of the active agent. In another aspect, the degree of drying is adjusted to comprise substantially complete intermediate drying, thereby resulting in an initial lag in release of the active agent and a substantially sigmoidal release of the active agent. In still a further aspect of the invention, the adjusting step comprises: performing a degree of intermediate drying of the microparticles; washing the microparticles; and performing final drying of the microparticles. In yet another aspect of the invention, the washing step comprises: introducing the microparticles into a vessel containing an extraction medium having a temperature lower than the glass transition temperature of the microparticles; agitating the vessel contents to disperse the microparticles in the extraction medium; and transferring the microparticles from the vessel to an extraction tank having another extraction medium having a temperature higher than the glass transition temperature of the microparticles at the time of transfer of the microparticles.
In still a further aspect of the present invention, a microencapsulated active agent having a selected release profile is provided. The microencapsulated active agent is prepared by a method for preparing microparticles, which method comprises: preparing an emulsion that comprises a first phase and a second phase, the first phase comprising the active agent, a polymer, and a solvent for the polymer, quenching the emulsion in a quench liquid to form microparticles containing the active agent; and performing a degree of intermediate drying of the microparticles so that the selected release profile of the active agent from the microparticles is achieved.
Features and Advantages
Advantages of the method of the present invention are that it provides, inter alia, a biodegradable, biocompatible system that can be injected into a patient, the ability to mix microparticles containing different active agents, and the ability to program release by preparing microparticles with selected release profiles and with multiphasic release patterns to give faster or slower rates of active agent release as needed.
A particular advantage of the method of the present invention is that it provides an additional parameter, the degree of intermediate drying, to control the release pattern or profile of microparticles. The method of the present invention is advantageous in that after such parameters as monomer size, coreload, and molecular weight have been determined, the release profile can be adjusted through the degree of intermediate drying.
An advantage of the products prepared by the method of the present invention is that durations of action ranging from several days to more than 200 days can be obtained, depending upon the type of microparticle and release profile selected. In preferred embodiments, the microparticles are designed to afford treatment to patients during duration of action periods of 30 to 100 days. A 60 day duration of action period is considered to be particularly advantageous. As readily apparent to one of skill in the relevant art, the duration of action can be controlled by manipulation of the polymer composition, polymer drug ratio, microparticle size, excipients, and concentration of residual solvent remaining in the microparticle.